tbuckley/cabot-search huggingface dataset:
Having it both ways: how STAT3 deficiency blocks graft-versus-host disease while preserving graft-versus-leukemia activity
Authors: Joshua D. Brandstadter, Riley Outen, Ivan Maillard
Journal: Journal of Clinical Investigation (2023)

Allogeneic hematopoietic cell transplantation can cure patients with high-risk leukemia through graft-versus-leukemia (GVL) effects, the process by which malignant leukemic cells are cleared by donor-derived immune cells from the graft. The problem of harnessing GVL effects while controlling inflammation and host-organ damage linked with graft-versus-host disease (GVHD) has been the most formidable hurdle facing allogeneic hematopoietic cell transplantation. This powerful, curative-intent therapy remains among the most toxic treatments in the hematologist's armamentarium due to the combined risks of GVHD-related morbidity, infections, and leukemia relapse. In this issue of the JCI, Li, Wang, et al. report that T cell Stat3 deficiency can extricate GVL effects from GVHD through tissue-specific programmed death-ligand 1/programmed cell death protein 1-dependent (PD-L1/PD-1-dependent) bioenergetic alterations that blunt harmful T cell effects in GVHD target organs, while preserving their beneficial antitumor activity in lymphohematopoietic tissues.
Author Correction: HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription
Authors: Peng Huang, Scott A. Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Cheryl A. Keller, Belinda Giardine, Henry W. Bell, Xianjiang Lan, Malini Sharma, John R. Horton, Osheiza Abdulmalik, Stella T. Chou, Junwei Shi, Merlin Crossley, Ross C. Hardison, Xiaodong Cheng, Gerd A. Blobel
Journal: Nature Genetics (2023)
Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology
Authors: Aaron R. Weiss, Yen-Lin Chen, Thomas J. Scharschmidt, Wei Xue, Zhengya Gao, Jennifer O. Black, Edwin Choy, Jessica L. Davis, Julie C. Fanburg-Smith, Simon C. Kao, Mark L. Kayton, Sandy Kessel, Ruth Lim, Lynn Million, Scott H. Okuno, Andrew Ostrenga, Marguerite T. Parisi, Daniel A. Pryma, R. Lor Randall, Mark A. Rosen, Barry L. Shulkin, Stephanie Terezakis, Rajkumar Venkatramani, Eduardo Zambrano, Dian Wang, Douglas S. Hawkins, Sheri L. Spunt
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867 ). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B ( P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B ( P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.
Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy
Authors: M Hope Robinson, Nancy Y Villa, David L Jaye, Ajay K Nooka, Alyssa Duffy, Samuel S McCachren, Julia Manalo, Jeffrey M Switchenko, Sierra Barnes, Sayalee Potdar, Maryam I Azeem, Ava A Horvat, Vaunita C Parihar, Jingjing Gong, Yan Liang, Geoffrey H Smith, Vikas A Gupta, Lawrence H Boise, Jonathan L Kaufman, Craig C Hofmeister, Nisha S Joseph, Sagar Lonial, Kavita M Dhodapkar, Madhav V Dhodapkar
Journal: Journal of Clinical Investigation (2023)

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell-rich and T cell-sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC-mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A-positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1-positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.
Foxm1 haploinsufficiency drives clonal hematopoiesis and promotes a stress-related transition to hematologic malignancy in mice
Authors: Chunjie Yu, Yue Sheng, Fang Yu, Hongyu Ni, Alan Qiu, Yong Huang, Zhijian Qian
Journal: Journal of Clinical Investigation (2023)

Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignancies. In patients with del(5q) myelodysplastic syndrome (MDS), the transcription factor FOXM1 is frequently downregulated in CD34+ cells. In this study, we demonstrated that Foxm1 haploinsufficiency disturbed normal hematopoiesis and conferred a competitive repopulation advantage for a short period. However, it impaired the long-term self-renewal capacity of hematopoietic stem cells, recapitulating the phenotypes of abnormal hematopoietic stem cells observed in patients with MDS. Moreover, heterozygous inactivation of Foxm1 led to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induced hematopoietic dysplasia in a mouse model with LPS-induced chronic inflammation and accelerated AML-ETO9a-mediated leukemogenesis. We have also identified Parp1, an important enzyme that responds to various types of DNA damage, as a target of Foxm1. Foxm1 haploinsufficiency decreased the ability of HSPCs to efficiently repair DNA damage by downregulating Parp1 expression. Our findings suggest that the downregulation of the Foxm1-Parp1 molecular axis may promote clonal hematopoiesis and reduce genome stability, contributing to del(5q) MDS pathogenesis.
Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death
Authors: Brent R Logan, Denggang Fu, Alan Howard, Mingwei Fei, Jianqun Kou, Morgan R Little, Djamilatou Adom, Fathima A Mohamed, Bruce R Blazar, Philip R Gafken, Sophie Paczesny
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDChronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT). More accurate information regarding the risk of developing cGVHD is required. Bone marrow (BM) grafts contribute to lower cGVHD, which creates a dispute over whether risk biomarker scores should be used for peripheral blood (PB) and BM.METHODSDay 90 plasma proteomics from PB and BM recipients developing cGVHD revealed 5 risk markers that were added to 8 previous cGVHD markers to screen 982 HCT samples of 2 multicenter Blood and Marrow Transplant Clinical Trials Network (BMTCTN) cohorts. Each marker was tested for its association with cause-specific hazard ratios (HRs) of cGVHD using Cox-proportional-hazards models. We paired these clinical studies with biomarker measurements in a mouse model of cGVHD.RESULTSSpearman correlations between DKK3 and MMP3 were significant in both cohorts. In BMTCTN 0201 multivariate analyses, PB recipients with 1-log increase in CXCL9 and DKK3 were 1.3 times (95% CI: 1.1-1.4, P = 0.001) and 1.9 times (95%CI: 1.1-3.2, P = 0.019) and BM recipients with 1-log increase in CXCL10 and MMP3 were 1.3 times (95%CI: 1.0-1.6, P = 0.018 and P = 0.023) more likely to develop cGVHD. In BMTCTN 1202, PB patients with high CXCL9 and MMP3 were 1.1 times (95%CI: 1.0-1.2, P = 0.037) and 1.2 times (95%CI: 1.0-1.3, P = 0.009) more likely to develop cGVHD. PB patients with high biomarkers had increased likelihood to develop cGVHD in both cohorts (22%-32% versus 8%-12%, P = 0.002 and P < 0.001, respectively). Mice showed elevated circulating biomarkers before the signs of cGVHD.CONCLUSIONBiomarker levels at 3 months after HCT identify patients at risk for cGVHD occurrence.FUNDINGNIH grants R01CA168814, R21HL139934, P01CA158505, T32AI007313, and R01CA264921.
Application of Global Lung Function Initiative Global Spirometry Reference Equations across a Large, Multicenter Pulmonary Function Lab Population
Authors: Amjad N. Kanj, Paul D. Scanlon, Hemang Yadav, William T. Smith, Tyler L. Herzog, Aaron Bungum, Daniel Poliszuk, Edward Fick, Augustine S. Lee, Alexander S. Niven
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a “race-neutral” interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives: Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race / ethnicity using GLI Global in place of GLI-2012 reference equations. Methods: In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared to the existing GLI-2012 standard, stratified by self-reported race / ethnicity. Measurements and Main Results: Mean FEV1 and FVC percent predicted increased in the Caucasian and Northeast Asian groups and decreased in the Black, Southeast (SE) Asian and Mixed / Other groups. The prevalence of obstruction increased by 9.7% in the Caucasian group, and that of possible restriction increased by 51.1% and 37.1% in the Black and SE Asian groups, respectively. Using GLI Global in a population with equal representation of all five race / ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in frequency of abnormal spirometry tests (32.9%). Conclusions: Use of GLI Global reference equations will significantly impact spirometry interpretation. While GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need for placing these data within an appropriate clinical context. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities
Authors: Matthew Moll, Anna L. Peljto, John S. Kim, Hanfei Xu, Catherine L. Debban, Xianfeng Chen, Aravind Menon, Rachel K. Putman, Auyon J. Ghosh, Aabida Saferali, Mizuki Nishino, Hiroto Hatabu, Brian D. Hobbs, Julian Hecker, Gregory McDermott, Jeffrey A. Sparks, Louise V. Wain, Richard J. Allen, Martin D. Tobin, Benjamin A. Raby, Sung Chun, Edwin K. Silverman, Ana C. Zamora, Victor E. Ortega, Christine K. Garcia, R. Graham Barr, Eugene R. Bleecker, Deborah A. Meyers, Robert J. Kaner, Stephen S. Rich, Ani Manichaikul, Jerome I. Rotter, Josée Dupuis, George T. O’Connor, Tasha E. Fingerlin, Gary M. Hunninghake, David A. Schwartz, Michael H. Cho
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case–control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10−95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10−87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.
Bridging Treatment Implementation Gaps in Patients With Heart Failure
Authors: Mohamed B. Jalloh, Tauben Averbuch, Prashanth Kulkarni, Christopher B. Granger, James L. Januzzi, Faiez Zannad, Robert W. Yeh, Clyde W. Yancy, Gregg C. Fonarow, Khadijah Breathett, C. Michael Gibson, Harriette G.C. Van Spall
Journal: Journal of the American College of Cardiology (2023)
Prognostic Performance of Right Ventricular Global Longitudinal Strain Measurements in Patients With Ebstein Anomaly
Authors: Alexander C. Egbe, William R. Miranda, C. Charles Jain, Kartik Andi, Omar Abozied, Ahmed Younis, Sriharsha Kandlakunta, Abdalla A. Salama, Elizabeth H. Stephens, Heidi M. Connolly
Journal: Journal of the American College of Cardiology (2023)
Indoor Pollution and Lung Function Decline in Current and Former Smokers: SPIROMICS AIR
Authors: Nadia N. Hansel, Han Woo, Kirsten Koehler, Amanda Gassett, Laura M. Paulin, Neil E. Alexis, Nirupama Putcha, Wendy Lorizio, Ashraf Fawzy, Daniel Belz, Coralynn Sack, R. Graham Barr, Fernando J. Martinez, MeiLan K. Han, Prescott Woodruff, Cheryl Pirozzi, Robert Paine, Igor Barjaktarevic, Christopher B. Cooper, Victor Ortega, Marina Zusman, Joel D. Kaufman
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression.
Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life
Authors: Nipasiri Voraphani, Debra A. Stern, Julie G. Ledford, Amber L. Spangenberg, Jing Zhai, Anne L. Wright, Wayne J. Morgan, Monica Kraft, Duane L. Sherrill, John A. Curtin, Clare S. Murray, Adnan Custovic, Inger Kull, Jenny Hallberg, Anna Bergström, Esther Herrera-Luis, Marilyn Halonen, Fernando D. Martinez, Angela Simpson, Erik Melén, Stefano Guerra
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: CC16 is an anti-inflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: TCRS (years 6-36; N-participants=814, N-observations=3042), BAMSE (years 8-24; Ns=2547, 3438), and MAAS (years 5-18, Ns=745, 1626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: 1) After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjOR per 1-SD CC16 decrease: 1.20[95%CI 1.12-1.28];P<0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjRRR: 1.40[1.24-1.57];P<0.0001), was confirmed for both atopic and non-atopic asthma, and was independent of lung function impairment. 2) After adjustment for known predictors of persistent asthma, asthmatic children in the lowest CC16 tertile had a nearly 4-fold increased risk for having frequent symptoms persisting into adult life, compared with asthmatic children in the other two CC16 tertiles (meta-analyzed adjOR: 3.72[1.78-7.76];P<0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through mid-adult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.
Genetic drivers in the natural history of chronic lymphocytic leukemia development as early as 16 years before diagnosis
Authors: P. Martijn Kolijn, Florentin Späth, Mouhamad Khouja, Paul J. Hengeveld, Lina van der Straten, Nikos Darzentas, Magnus Hultdin, James D. McKay, Christiane Pott, Roel C. H. Vermeulen, Anton W. Langerak
Journal: Blood (2023)

ATM variants and IGLV3-21R110 are early events in CLL pathogenesis, while NOTCH1, SF3B1, and XPO1 variants arise later.
In relapsing AAV with rituximab-induced remission, maintenance rituximab vs. azathioprine reduced relapse at ≥32 mo
Authors: David S. Pisetsky
Journal: Annals of Internal Medicine (2023)

Source Citation Smith RM, Jones RB, Specks U, et al; RITAZAREM co-investigators. Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial. Ann Rheum Dis. 2023;82:937-944. 36958796
Cardiovascular Assessment up to One Year After COVID-19 Vaccine–Associated Myocarditis
Authors: Clement Kwong-man Yu, Sabrina Tsao, Carol Wing-kei Ng, Gilbert T. Chua, Kwok-lap Chan, Julia Shi, Yumi Yuk-ting Chan, Patrick Ip, Mike Yat-wah Kwan, Yiu-fai Cheung
Journal: Circulation (2023)
A Redox Modulatory SOD Mimetic Nanozyme Prevents the Formation of Cytotoxic Peroxynitrite and Improves Nitric Oxide Bioavailability in Human Endothelial Cells
Authors: Motika Geethika, Namrata Singh, Sagar Kumar, Somanathapura K. Naveen Kumar, Govindasamy Mugesh
Journal: Advanced Healthcare Materials (2023)

The endothelium-derived signalling molecule nitric oxide (NO) in addition to controlling multifarious servo-regulatory functions, suppresses key processes in vascular lesion formation and prevents atherogenesis and other vascular abnormalities. The conversion of NO into cytotoxic and powerful oxidant peroxynitrite (ONOO- ) in a superoxide (O2.- )-rich environment has emerged as a major reason for reduced NO levels in vascular walls, leading to endothelial dysfunction and cardiovascular complications. So, designing superoxide dismutase (SOD) mimetics that can selectively catalyze the dismutation of O2.- in the presence of NO, considering their rapid reaction is challenging and is of therapeutic relevance. Herein, the authors report that SOD mimetic cerium vanadate (CeVO4 ) nanozymes effectively regulate the bioavailability of both NO and O2.- , the two vital constitutive molecules of vascular endothelium, even in the absence of cellular SOD enzyme. The nanozymes optimally modulate the O2.- level in endothelial cells under oxidative stress conditions and improve endogenously generated NO levels by preventing the formation of ONOO- . Furthermore, nanoparticles exhibit size- and morphology-dependent uptake into the cells and internalize via the clathrin-mediated endocytosis pathway. Intravenous administration of CeVO4 nanoparticles in mice caused no definite organ toxicity and unaltered haematological and biochemical parameters, indicating their biosafety and potential use in biological applications.
Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance
Authors: Ruth Nussinov, Hyunbum Jang
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-Ras G12C . Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-Ras G12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in cis, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights into pharmacology and resistance.